Magnetic resonance imaging (MRI) is a uniquely informative soft tissue imaging modality with contrast that is sensitive to a myriad of physical, chemical, and functional characteristics of tissue but often lacks specificity. On the spatial scale relevant to water proton (1H) nuclear magnetic resonance (NMR), tissues are heterogeneous and, consequently, exhibit an NMR signal that is the complex summation of spatially varying characteristics. Most MRI protocols provide contrast between tissues that can be resolved spatially, but yield little or no quantitative information about the variation in NMR signal that exists on a smaller scale, that is, the sub-voxel scale. This quantitative sub-voxel information is alluring because it provides specificity to tissue micro-anatomy. Development of quantitative sub-voxel MRI tissue characterization requires coordinated advancement on two fronts: 1) quantitative models that relate relevant micro-anatomical characteristics to 1H NMR signal characteristics, and 2) practical and effective quantitative MRI methods that can translate these the use of sub-voxel tissue models to widespread utility for researchers and clinicians. The proposed studies address both modeling and method development with the aim to develop practical and quantitative imaging biomarkers for micro-anatomical characteristics of white matter and skeletal muscle, including 1) myelin volume fraction and myelin thickness in normal, developing, and abnormally developing white matter, and 2) myofiber volume fraction and size, in the presence of inflammation and fibrosis. Such biomarkers have the potential to impact research and clinical diagnostics by providing quantitative and specific measures to track changes in disorders associated with abnormal white matter development, such as Schizophrenia and Autism, as well muscle injuries and diseases such as Muscular Dystrophy. PUBLIC HEALTH RELEVANCE: MRI is a widespread diagnostic imaging modality capable of relatively non-invasive visualization of soft tissue. The contrast in MRI results from many complex interactions of water molecules in the body with each other and the physical and chemical characteristics of their local environments. This research program aims to better relate MRI contrast to specific micro-anatomical characteristics in neural tissue and skeletal muscle. This work has broad potential impact the diagnostic and prognostic capabilities of MRI for a wide array of diseases and injuries.